This is a proposal to explore the role of RNA dysregulation in the pathogenesis of amyotrophic lateral sclerosis (ALS). The work stems from recent findings that rare patients with familial ALS have mutations in RNA binding proteins. We will use newly developed methods to look at normal and abnormal RNA-protein interactions in tissues obtained from mouse models of ALS and from human ALS samples obtained at autopsy. This work has the potential to uncover new insights, as well as diagnostic markers and therapeutic targets for ALS. In addition, the use of new methods and paradigms will serve as a model for how to approach a growing list of neurologic disorders associated with RNA dysregulation. PUBLIC HEALTH RELEVANCE: This work is a study of a currently fatal human neurologic disorder that currently affects over 20,000 Americans. There is no means of diagnosing the disease short of clinical examination, and there is no treatment. The work offers the hope of understanding the cause, and of developing diagnostic markers and therapeutic targets for the disorder.